19-nor steroids substituted in position 11β, preparation method and intermediates, application as medicines and pharmaceutical compositions containing them

ABSTRACT

A compound selected from the group consisting of the compounds of the formulawherein the substituents are defined as in the specification and their addition salts with non-toxic, pharmaceutically acceptable acids and bases having estrogenic activity at the bone level but little or no endometrial hyperplasia activity nor any activity for proliferation of mammary tumors.

This application is a 371 of PCT/FR98/02437 filed Nov. 16, 1998.

The present invention concerns 19-nor steroid compounds, substituted inposition 11β, their preparation process and intermediates, theirapplication as medicines and the pharmaceutical compositions containingthem.

Osteoporosis is a pathology that is characterised by a quantitative andqualitative reduction of the bone tissue, sufficient to lead tovertebral or peripheral fractures, in a spontaneous manner or withminimum traumatism. Although this ailment is of multifactorial origin,it is the menopause that, in women, constitutes the dominating factor ofbone loss or osteopenia.

This osteopenia shows itself by rarefaction and modification of thestructure of spongy bone which has the consequence of accentuatingskeletal fragility and the risk of fracture. The bone loss stronglyaccentuates after the menopause because of the suppression of ovarianfunction and reaches 3 to 5% per year to slow down after the age of 65years.

In a therapeutic objective, postmenopausal hormonal deficiency can becompensated by hormone replacement therapy where oestrogen plays a majorrole in preserving the bone reserves. But long term oestrogen therapy issometimes accompanied by undesirable effects on the genital organs(endometrial hyperplasia, mammary tumours), this constitutes a majordrawback and limits its application.

It is thus advisable to find other compounds than oestradiol with adissociated oestrogen activity, namely oestrogen activity at bone level,whilst having little or no endometrial hyperplasia activity, nor theactivity of proliferating mammary tumours.

The invention thus has as its object the compounds of general formula(I):

in which:

R₁ represents a hydrogen atom, a (CH₂)_(m)-Ar, (CO)-Ar, (CH₂)_(m)-Alk or(CO)-Alk radical,

R₂ represents a radical derived from a saturated or unsaturated, linearor branched hydrocarbide containing from 1 to 6 carbon atoms

D represents the residue of a pentagonal or hexagonal ring optionallysubstituted and optionally unsaturated,

X represents a halogen or hydrogen atom, n is equal to 3, 4 or 5, eitheridentical or different R₃ and R₄ representing a hydrogen atom, a(CH₂)_(m)-AR, (CH₂)_(m)-Het or (CH₂)_(m)-Alk group,

or R₃ and R₄ together with the nitrogen atom to which they are linkedform an aromatic or non aromatic, saturated or unsaturated mono orpolyclique heterocycle, with 3 to 15 bonds optionally containing from 1to 3 additional heteroatoms chosen from amongst non substituted orsubstituted oxygen, sulphur and nitrogen,

Ar representing a carbocyclic aryl group containing from 6 to 18 atomsof carbon, Het representing a saturated or unsaturated aromatic or nonaromatic heterocycle, comprising from 1 to 9 carbon atoms and from 1 to5 heteroatoms chosen from amongst oxygen nitrogen or sulphur atoms, Alkrepresenting a radical derived from a non aromatic, linear, branched orcyclique, saturated or unsaturated hydrocarbide and comprising from 1 to12 carbon atoms, the Ar radicals Het or Alk can be substituted or nonsubstituted, m represents 0, 1, 2 or 3, as well as their addition saltswith the bases or the acids.

By halogen is meant: iodine, bromine, chlorine or fluorine.

By (CH₂)_(m) is meant the following values: single bond in the eventthat m is equal to 0, CH₂, (CH₂)₂ and (CH₂)₃.

By the term Ar representing the carbocyclic aryl group containing from 6to 18 carbon atoms, is meant an aromatic cyclic hydrocarbide derivativesuch as the phenyl, naphtyl, phenanthrenyl radical or even a condensedbicyclic or tricyclic hydrocarbide derivative comprising a benzene ringlike indanyl, indenyl, dihydronaphtyl, tetrahydronaphtyl or fluorenyl.The coupling is made at the benzene ring. It preferably concerns phenyl.

By the term (Het) representing an aromatic or non aromatic, saturated orunsaturated heterocycle, comprising from 1 to 9 carbon atoms and from 1to 5 heteroatoms chosen from amongst oxygen, nitrogen and sulphur atomsthese are notably designated:

Heterocyclic monocyclic radicals, for example thienyl, furyl, pyrannyl,pyrrolyl, imadazoyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl,pyrazolinyl, thiazollinyl, triazolyl, tetrazolyl,

the heterocyclic condensed rings, for example benzofurannyl,benzothienyl, benzimidazoyl, benzothiazolyl, naphto [2,3-b] thienyl,thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl,indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,quinolizinyl, isoquinolyl, quinolyl, phtalazinyl, naphtyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl radicals oreven condensed polycyclic systems, made up of monocyclic heterocyclicslike those defined above like for example furo[2,3-b]pyrrol orthieno[2,3-b]furan,

or saturated heterocycles such as pyrrolidine, piperidine andmorpholine.

By the term (Alk) representing a radical derived from a saturated orunsaturated, branched or cyclic, linear, non aromatic hydrocarbide, aredesignated, in the case of acyclic hydrocarbides alkyl radicals such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl,2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl,2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl3-ethylpentyl, nonyl,2,4-dimethylheptyl or n-decyl, radical alkenyls such as vinyl, propenyl,isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynylradicals such as ethynyl, propynyl,propargyl, butynyl or isobutynyl, andin the case of cyclic radicals, the cycloalkyl radicals, such ascyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Preferably methyl and ethyl radicals are used.

By CO-Alk is preferably meant COCH₃ and COEt, by CO-Ar is preferablymeant the benzoyl radical, when m is different to zero, (CH₂)_(m)-Arwill preferably be the benzyl group.

When R₃ and R₄ together with the nitrogen atom to which they are linkedform a heterocycle, they are notably mono or bicyclic heterocyclesoptionally containing another heteroatom chosen from amongst oxygen andnitrogen such as the following unsaturated heterocycles: pyrrolyl,imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,thiazolyl, oxazoyl, furazolinyl, pyrazolinyl, thiazolinyl, or moreparticularly, the following saturated heterocycles:

When the different Alk, Ar, Het groups as well as the residue of apentagonal or hexagonal ring cited earlier are substituted, they couldnotably be so by the following radicals: halogen, namely fluorine,chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propyloxy,isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio,propylthio, isopropylthio, butylthio, amino, alkylamino such asmethylamino or ethylamino, dialkylamino such as dimethylamino,diethylamino, methylethylamino, each of these dialkylamino radicalsbeing optionally in oxidised form, aminoalkyl such as aminoethyl oraminoethyl, dialkylaminoalkyl such as dimethylamino methyl or ethyl,dialkylaminoalkyloxy such as dimethylamino ethyloxy, optionally acylatedhydroxyl, acyl such as acetyl, propionyl, butyryl, benzoyl, freecarboxy, esterified like alkoxy carbonyl for example methoxy carbonyl orethoxy carbonyl, cyano, trifluoromethyl, aryl such as phenyl, aralkylsuch as benzyl, alkyl, alkenyl or alkynyl these radicals beingthemselves optionally substituted by the halogen, alkyl, alkoxy,alkylthio, amino, alkylamino or dialkylamino radicals indicated above.

Of course, the expression “substituted” indicates that one or severalidentical or different substitutes, can be present. As an example, whenthe alkyl group is a methyl radical substituted by one or severalhalogen atoms, it can notably be CH₂Cl, CH₂F, CHF₂ and CF₃.

In the case of (Het), the substitutes can be at the level of NH or of acarbon atom.

Of course the values of R₁, R₂, R₃, and R₄, are independent from eachother.

The invention naturally extends to the salts of the compounds of formula(I), like for example the salts formed with mineral or organic acids onthe amine. It can thus concern chlorohydric, bromhydric, nitric,sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic,fumaric, succinic, tartric, citric, oxalic, glyoxylic, aspartic, alcanesulfonic acids such as methane or ethane, sulfonic, arylsulfonic acids,like the sulfonic and arylcarboxylic benzene or paratoluene acids. Whenthe compounds of formula (I) include an acid function, the inventionextends to the optionally substituted salts of alkaline, earthy alkalineor ammonium metals.

The invention more particularly has as its object the compounds ofgeneral formula (I) as described above, in which (D) represents theresidue of a pentagonal ring of formula:

in which

R₂ retains the same signification as before,

either R₅ represents an OH, O—(CH₂)_(m)-Alk, O—(CO)-Alk,O—(CH₂)_(m)-Ar,O—(CO)-Ar,O—(CH₂)_(m)-Het, O—(CO)-Het and R₆ represents ahydrogen atom, an alkyl, alkenyl or alkynyl radical containing from 1 to6 substituted or non substituted carbon atoms, m, Alk, Ar and Het aspreviously described,

or R₅ and R₆ together with the carbon atom which carries them form inone of the following rings:

 in which

z represents a—(CH₂)₁—or—CH═CH—(CH₂)_(1′ group,) 1 being an integerbetween 1 and 4 and 1′being an integer equal to 1 or 2,

either R₅ and R₆ together form an oxo group, as well as their additionsalts with the acids or the bases.

The invention has more particularly as its object the compounds offormula (I) as previously described corresponding to general formula(I′):

in which:

X represents a chlorine, bromine or hydrogen atom, n′ is equal to 3,

or identical or different R′₃ and R′₄ represent an alkyt radicalcontaining from 1 to 6 carbon atoms

or R′₃ and R′₄ together, with the atom of nitrogen to which they arelinked, form a saturated mono or polyclic residue with 3 to 15 bondsoptionally containing an additional heteroatom chosen from amongstoxygen, sulphur and nitrogen,

R′₅ and R′₆ have the same signification as R₅ and R₆,

as well as their addition salts with the acids and the bases.

The invention has more particularly as its object the compounds offormula (I) as previously described corresponding to general formula(I′) in which:

either R′₅ represents an OH radical and R′₆ a hydrogen atom, an alkyl,alkenyl or alkynyl radical containing from 1 to 6 substituted or nonsubstituted carbon atoms,

or R′₅ and R′₆ together with the carbon atom which carries them form oneof the following rings:

 or R′₅ and R′₆ together form an oxo group, as well as their additionsalts with the acids or the bases.

The invention has more particularly as its object the compounds offormula (I) corresponding to general formula (I′) as previouslydescribed in which:

X′ represents a chlorine or hydrogen atom,

n′ is equal to 3,

either identical or different R′₃ and R′₄ represent an alkyl radicalcontaining from 1 to 6 carbon atoms

or R′₃ and R′₄ together with the nitrogen atom form the followingsaturated heterocycles:

 and either R′₅ represents an OH radical and R′₆ represents a hydrogenatom,

an alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbonatoms, substituted or not,

or R′₅ and R′₆ together with the carbon atom which carries them form oneof the following rings:

 or R′₅ and R′₆ together form an oxo group,

as well as their addition salts with the acids or the bases.

The invention has more particularly as its object either the compoundsof general formula (I) as previously described in which X═H, or thecompounds of general formula (I) as previously described in which X═Clor Br, and more particularly Cl.

The invention has very particularly as its object the compounds offormula (I) as well as their addition salts with the acids whose namesare the following:

3-hydroxy-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one,

3-hydroxy-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one,

3-hydroxy-11β-[4-[3-dimethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-17-one,

4-chloro-3-hydroxy-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

4-chloro-3-hydroxy-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

4-chloro-3-hydroxy-11β-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol,

11β-[4-(3-dimethylamino)propyl)phenyl]-estra-1,3,5(10)-trien-3,17β-diol

11β-[4-(3-(1-piperidinyl)propyl)phenyl]-estra-1,3,5(10)-trien-3.17β-diol

4-chloro-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β- diol

4-chloro-11β-[4-[3-(1-piperidinyl)propyl(]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

4-chloro-11β-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol,

17α-methyl-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol,

4-chloro-17α-methyl-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-[diol

11β-[4-[3-(1-piperidinyl)propyl]phenyl]-17α-(trifluoromethyl)-estra-1,3,5(10)-trien-3,17β-diol]

(17R)11β-[4-(3-dimethylamino)propyl)phenyl]-spiro-(estra-1,3,5(10)-trien-17,2′(5′H)-furan)-3-ol

(17R)4′.5′-dihydro-11β-[4-(3-dimethylamino)propyl)phenyl]-spiro-(estra-1,3,5(10)-trien-17,2′(3′H)-furan)-3-ol.

The invention equally has as its object a preparation process for thecompounds of formula (I) as previously described in which a compound offormula (II) is submitted:

in which

D and R₂ are as previously described and K represents a protector groupof 3-ceto function, successive to the following reactions:

a) action of a formula (III) compound:

 in which, M represents a metallic derivative, P represents an alcoholprotector group and n is an integer equal to 3, 4 or 5, then optionallydeprotection of one or several protected reagent functions, in order toobtain a formula (III_(a)) compound:

 P′ having the same values as P as well as hydrogen,

b) action, optionally, of a halogenation reagent, in order to obtain aformula (III_(b)) compound:

 Hal representing a halogen atom,

c) after having optionally protected and/or activated the OH function,action of an aromatisation reagent of ring (A) on the formula (III_(a))and (III_(b)) compounds, then action of a base to obtain the formula(IV) compound:

 P″ having the same values as p′ and able moreover to represent anactivating group,

X being as previously described,

d) action of a formula (V) amine:

 R₃ and R₄ being as previously defined, this compound optionally beingin the form of a salt, in order to obtain certain compounds of formula(I), the compounds of formulas (III_(a)), (III_(b)), (IV) and (I) beingsubmitted if desired or if necessary, in a suitable order, to one orseveral of the following reactions:

protection/deprotection of the OH group(s),

alkylation/acylation of the OH group(s),

action of a reduction agent when D represents the residue of apentagonal ring as previously described and R₅ and R₆ together form anoxo group,

action of an organometallic or CF₃SIMe₃ on the compounds of formula (IV)or (I) with D representing the residue of a pentagonal ring aspreviously described and R₅ and R₆ together forming an oxo group,

action of a lactonisation agent on the compounds of formula (IV) or (I)with D representing the residue of a pentagonal ring as previouslydescribed and R₅ and R₆ together forming an oxo group,

action of a reduction agent of the double bond, when D represents theresidue of a pentagonal ring as previously described and R₅ and R₆together with the carbon that carries them, form an O—(CH₂)_(1′)—CH═CH—,

action of a reduction agent, when D represents the residue of apentagonal ring as previously described, and R₆ is an alkenyl or alkynylradical containing from 2 to 6 carbon atoms,

salification.

The action of a compound of formula (III) on the compound of formula(II) is preferably carried out in the presence of a copper salt such ascopper chloride I.

The action of a halogenation reagent such as N-bromosuccinimide orN-chlorosuccinimide on the compounds of formula (III_(a)) is notablycarried out in the presence of a dipolar aprotic solvent such asdimethylformamide.

The reaction of aromatisation followed by the reaction of saponification(basic action) is carried out according to standard methods such as aredescribed in European patent 0097572. Preferably a compound of aceticanyhydride and acetyl bromide is used as aromatisation agent then a basesuch as soda in methanol as saponification agent.

By activation of the alcohol is meant the introduction notably of amesylate, tosylate or triflate which makes it possible to facilitate thenucleophile substitution of the amine of formula (V) on the compounds offormula (IV). The formation of the mesylate, tosylate or triflate fromcompounds of formula (III_(a)) or (III_(b)) with P′ representinghydrogen is carried out in the presence of a base such as triethylamine.

The substitution of alcohol with a halogen atom can equally beenvisaged.

The protection and deprotection reactions are standard methods known toa specialist. A quite comprehensive review is found in the followingwork: Protective groups in organic synthesis T. W. Greene, John Wiley &sons (1981).

The protector group P can represent an alkyl radical containing from 1to 4 carbon atoms, a benzyl group, a tetrahydropyrannyl group, anR_(C)R_(D)R_(E)Si group, in which identical or different R_(C),R_(D) andR_(E), independently from one another each represent an alkyl radicalcontaining from 1 to 4 carbon atoms or a phenyl group. It particularlyconcerns the Si(Me)₂C_(me3) or—Si(PH)₂CMe₃ or SiMe₃ groups.

As an example, the deprotection reactions of the compounds of formula(III_(a)) or (III_(b)), when P′ is a tertbutyldiphenylsilyl group can becarried out by the action of ammonium tetrabutyl fluoride in solution intetrahydrofuran.

When P′ is a tetrahydropyrannyl group, the deprotection is carried outin the presence of an aqueous acid in an alcoholic solvent andpreferably by the action of chlorohydric acid in methanol.

The action of a compound of formula R₃—NH—R₄ on the compounds of formula(IV) is carried out in standard conditions of nucleophile substitutions,notably in the presence of an aprotic solvent such as tetrahydrofuran,OP″ thus preferably represents an O—SO₂CH₃, OSO₂—PH—pMe, OSO₂CPh₃. OPcan equally represent halogen (preferably bromine or iodine).

The alkylisation or acylsation reactions of the OH group in position 3or 17 are carried out by standard methods known to the specialist.

The reduction of 17-ceto in a corresponding alcohol (R₅=OH and R₆=H) iscarried out according to standard methods, notably by the action of analkaline borohydrure such as sodium borohydrure in methanol or ethanolor by action of aluminium and lithium tetrahydrure.

The action of an organometallic on the 17-ceto makes it possible to haveaccess to the products of formula (I) in which D represents the residueof a pentagonal ring as previously described, R₅ is hydroxyl and R₆represents an alkyl, alkenyl, optionally substituted alkynyl radical.

The organometallic derived from an alkyl, alkenyl or alkynyl is chosenfrom amongst the magnesians of formula AlkMgHal and the lithiens offormula AlkLi in which Alk represents an alkyl, alkenyl or alkynyl groupcontaining at the most 8 carbon atoms and Hal represents a halogen atom.In a preferred method of carrying out the process, Hal represents achloride, bromine or iodine atom, preferably bromine.

The reaction preferably takes place in the presence of cerium chloride.In a preferred method of carrying out the process Hal represents achloride, bromine or iodine atom, preferably bromine.

To obtain the compounds of formula (I) with R₅ is a hydroxyl and R₆ is aCF₃ group, the reaction is carried out by action of CF₃SiMe₃ on the17-ceto, followed by the action of a deprotection reagent such asammonium tetrabutyl fluoride.

The lactonisation reaction starting with 17 ceto is carried outaccording to the STURTZ method (ref: G STURTZ and J-J. YAOUANC,synthesis, (1980), 289) notably in the presence of allylbisdimethylamidophosphate in the presence of an alkyllithien such asN-butyllithium in tetrahydrofuran.

The reaction of total or partial reduction when R₆ is an alkenyl oralkynyl radical or when R₅ and R₆ together with the carbon that carriesthem, form an O—(CH₂)_(1′)—CH═CH—group, can be carried out eithertotally by the action of hydrogen in the presence of a catalyst such aspalladium on carbon or a rhodium catalyst such as Wilkinson's reagent orpartially (alkynyl becomes alkenyl) by the action of a poisoned catalystsuch as palladium on barium sulphate poisoned by pyridine ortriethylamine.

The reactions of esterification and salification are carried out bystandard methods known to the specialist.

The invention has more particularly as its aim a process for preparingcompounds of formula (I′) as previously described, in which a compoundof general formula (II′) is submitted:

in which

K, R′₅ and R′₆ are as previously described, or in which R′₅ is a CNradical and R′₆ is a protected hydroxyl, successive to the followingreactions:

a) action of a compound of formula (III′):

 in which M and P are as previously described, then deprotection of oneor several of the protected reactive functions, in order to obtain acompound of formula (III′_(a)):

b) action, optionally, of a halogenation reagent in order to obtain acompound of formula (III′_(b)):

 Hal′ representing a chlorine or bromine atom,

c) activation of the OH function then action of an aromatisation reagentof ring (A) on the compounds of formula (III_(a)) or (III_(b)), then theaction of a base to obtain the compounds of formula (IV′):

 X′ and P″ are as previously described,

d) action of an amine of formula (V′):

 R′₃ and R′₄ as previously described in order to obtain certaincomponents of formula (I′), the compounds of formulas (III′_(a)),(III′_(b)), (IV′) and (I′) submitted, if desired or if necessary to oneor several of the following reactions:

protection/deprotection of the OH group(s),

alkylation/acylation of the OH group(s),

action of a reduction agent when R′₅ and R′₆ together form an oxo group,

action of an organometallic or CF₃SiMe₃ on the compounds of formula(IV′) or (I′) with R′₅ and R′₆ together forming an oxo group,

action of a lactonisation agent on the compounds of formula (IV′) or(I′) with R′₅ and R₆ together forming an oxo group,

action of a reduction agent of the double bond, when R′₅ and R′₆together with the carbon that carries them, form anO—(CH₂)_(1′)—CH═CH—group,

action of a reduction agent, when R′₆ is an alkenyl or alkynyl radicalcontaining from 2 to 6 carbon atoms,

salification.

The compounds of general formula (I) as well as their addition saltswith pharmaceutically acceptable acids notably having oestrogen,anti-oestrogen and antiproliferative activities.

As such, the compounds of formula (I) can be used in the treatment ofdisorders linked to hypofolliculitis, for example amenorrhea,dysmenorrhea, repeated abortions, premenstrual disorders, in thetreatment of certain oestrogen dependent pathologies such as prostaticadenomas or carcinomas, mammary carcinomas and its metastases or thetreatment of benign breast tumours, as anti-uterotrophic as well as inthe hormone replacement treatment of the menopause or perimenopause.

Amongst the symptoms and the consequences linked to the menopause, aremore precisely meant the hot flushes, sweats, vaginal atrophia anddryness, urinary indications and in the long term lessening of bone massand the increase of the risk of fracture, as well as the loss of thecardio-vascular protection offered by oestrogens.

In particular, the compounds of formula (I) as well as their additionsalts with pharmaceutically acceptable acids or the bases can thus beused in the prevention or the treatment of osteoporosis.

The compounds of formula (I) as well as their addition salts withpharmaceutically acceptable acids or bases, can equally be used in theprevention or treatment of osteoporosis in men.

They can equally be used in the prevention or the (for example cortisoneor connected with immobilisation) treatment of secondary osteoporosis.

The compounds of formula (I) as well as their addition salts withpharmaceutically acceptable acids or bases notably have a dissociatedoestrogenic activity.

By dissociated oestrogenic activity, is meant oestrogenic activity atbone level whilst only manifesting a minimal activity at uterine levelthus leading to the absence of endometrial proliferation (activity wellbelow that of oestradiol).

Furthermore, the compounds according to the invention present thefollowing advantages:

They show an anti-oestrogen and/or antiproliferative activity in thebreast. Unlike oestradiol they do not stimulate the growth of humanmammary tumour cells and can even inhibit their growth. The compoundsaccording to the invention are thus particularly advantageous for thetreatment of the menopause as far as women at risk from mammary cancerare concerned (prior family history) who are thus excluded fromreplacement oestradiol treatment.

They can equally be used in the treatment of mammary cancers.

They lead to a lowering in the level of serum cholesterol to an at leastequivalent level of that induced by oestradiol. They thus reinforcecardiovascular protection.

Finally these compounds according to the invention do not show anyoestrogen activity at uterine level, do not need to be administered inassociation with a progestomimetic compound.

The invention thus has as its object the compounds of formula (I) aswell as their addition salts with pharmaceutically acceptable acids orbases, as medicines.

The invention has more particularly as its object the compounds offormula (I) as well as their addition salts with the pharmaceuticallyacceptable acids or bases, as medicines intended for the prevention ortreatment of osteoporosis.

The invention extends to pharmaceutical compositions containing asactive ingredient at least one of the medicines as described above.

The compounds of formula (I) are used by digestive, parenteral or localroute, for example by percutaneous route. They can be prescribed in theform of simple tablets or sugar coated pills, capsules, granules,suppositories, pessaries, injectable preparations, ointments, creams,gels, microspheres, implants, intravaginal rings, patches, which areprepared according to usual methods.

The active ingredient(s) can be incorporated into excipients usuallyused in these pharmaceutical compositions, such as talc, gum arabic,lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous mediums, fatty bodies of animal or vegetable origin, paraffinderivatives, glycols, various dilution, dispersant or emulsifyingagents, preservatives.

The useful dosage varies according to the condition to be treated andthe administration route; it can vary for example from 1 to 1000 mg perday in adults by oral route.

The compounds of general formula (II) or (II′) are compounds known anddescribed in the European Patent 0057115.

The compounds of formula (III) are known or are easily accessible to thespecialist starting with the corresponding aromatic halides. The aminesof formula (V) are equally known or easily accessible to a specialist.

The invention equally has as its aim, as intermediary products, thecompounds of formula (III_(a)), (III_(b)), (III′_(a)), (III_(b)), (IV)or (IV′).

The examples below illustrate the invention without at the same timelimiting it.

Solvents described in the examples: AcOEt (ethyl acetate), TEA(triethylamine), CH₂Cl₂ (dichloromethane), CHCl₃ (chloroform), MeOH(methanol), NH₄OH (ammonium hydroxide), iPrOH (isopropyl alcohol).

Preparation 1 11β-[4(3-hydroxypropyl)phenyl]-estra-4,9-diene-3,17-dione

Stage A: Alkylation

3-(4-bromophenyl)-2-propynol

To a solution under inert gas of 55.2 g of 4-bromo iodo benzene at 97%in 230 ml of DMF, 56 ml of TEA is added, 12.2 ml of propargylic alcohol,1 g of copper iodide and 1.1 g of PdCl₂ (PPh₃)₂ whilst maintaining thetemperature at 47° C. After stirring for 3 hours 15 minutes at ambienttemperature, it is poured into water, drawn off, washed dried andevaporated under reduced pressure until 48.3 g of raw product isobtained that is purified by chromatography on silica by eluting withthe compound CH₂Cl₂/AcOEt 95/5. 36, 37 g of expected pure product isobtained. (F=80° C.)

Rf (CH₂Cl₂/AcOEt 95/5): 0.32

IR (CHCl₃)

OH 3609cm⁻¹

C═C 2240 cm⁻¹

Aromatic 1585 and 1486 cm⁻¹

Stage B: Reduction

3-(4-bromophenyl)-propanol

To a solution under inert gas of 36.4 g of 3-(4-bromophenyl)-2-propynol(stage A) in 200 ml of ethanol at 5% of toluene, is added 200 ml oftoluene, 7.9 g of Wilkinson's reagent and hydrogen at 1900 mbar for 5hours. It is evaporated at reduced pressure until the obtainment of 45.9g of raw product that is purified by chromatography on silica by elutingwith the compound CH₂Cl₂/AcOEt 95/5. 30.1 g of expected product isobtained.

Rf (CH₂Cl₂/AcOEt 95/5): 0.28

IR (CHCl₃)

OH 3626 cm⁻¹

Aromatic 1592 and 1489 cm⁻¹

Stage C: Protection of the Alcohol

(1.1-dimethylethyl)dimethyl[[3-(4-bromophenyl)propyl]oxy]silane

To a solution under inert gas of 30.1 g of 3-(4-bromophenyl)-propanol(stage B) in 300 ml of CH₂Cl₂ is added 11.4 g of imidazol and 23 g ofdimethylterbutylsilyl chloride. After stirring for 45 minutes at ambienttemperature, it is washed in water, dried and evaporated under reducedpressure until 47.46 g of raw product is obtained that is purified(after having added 1.5 g of an identical trial) by redistillation. 44.8g of expected pure product is obtained.

Rf (CH₂Cl₂/AcOEt 95/5): 0.8

IR (CHCl₃)

OSi 1527 cm⁻¹ and 836 cm⁻¹

Aromatic 1590 cm⁻¹(f) and 1489 cm⁻¹

Stage D: Introduction of the Aryl Group in Position 11 of the Steroid

11β-[4-(3-hydroxypropyl)phenyl]-estra4.9-diene-3,17dione

Preparation of the Magnesian

To 2.67 g of magnesium (shavings) in 5 ml of THF under inert atmosphereand at ambient temperature, is added in 50 minutes at the reflux afterpriming to 1.2-dibromoethane, a solution of 32.9 g of(1.1-dimethylethyl)dimethyl[[3-(4-bromophenyl)propyl]oxy]silane (stageC) in 100 ml of THF and maintained 5 hours at reflux. (Heading byiodometry: 0.86 M)

Epoxide Opening

To the compound made up of 120 ml of magnesian, obtained at thepreceding stage and 600 mg of copper chloride, under inert atmosphere at0-5□Ca solution of 17.18 g of5α,10α-epoxy-3.3-[1.2-ethanediylbis(oxy)]-17α-[(trimethylsilyl)oxy]-estr-9(11)-ene-17α-carbonitrileis added (prepared according to the method described in J. C. Gasc andL. Nedelec Tetrahedron Letters (1971), 2005) in 100 m of THF, stirredfor 45 minutes at this temperature then poured into a solution ofammonium chloride, drawn off, washed and evaporated under reducedpressure until 43.5 g of raw product is obtained.

Acid Hydrolysis

To a solution of 43.5 g of product obtained from the preceding stage in300 ml of methanol, under inert atmosphere and at ambient temperature,60 ml of chlorhydric acid 6 m is added and stirred for 1 hour at ambienttemperature. After distillation of the methanol, ethyl acetate is added,it is washed, dried and evaporated under reduced pressure until 30 g ofraw product is obtained (F=254° C.).

Cleaving of the Cynhydrine

To a solution of 30 g of product obtained at the preceding stage in 200ml of methanol, under inert atmosphere and at ambient temperature, 8 mlof washing soda is added and stirred for 1 hour at ambient temperature.After distillation of the methanol, ethyl acetate is added, it iswashed, dried and evaporated under reduced pressure until 27.9 g of rawproduct is obtained that is firstly purified by chromatography byeluting with the compound CH₂Cl₂/MeOH 95/5. 13 g of expected product(F=192° C., Rf (CH₂Cl₂/MeOH 95/5): 0.28) is then obtained by dissolvingin a compound of 70 ml of CH₂Cl₂/and 70 ml of isopropylic ether that isconcentrated to crystallisation. 11.92 g of pure expected product isobtained.

F = 192° C. RMN (CDCl3 300 MHZ) 0.55(s) CH₃ in 18 ˜1.33 OH ˜3.66(m) CH₂—OH 4.41(d) H11 5.80(s) H4

EXAMPLE13-hydroxy-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

Stage A: Formation of Mesylate

11β-[4-[3-[(methylsulfonyl)oxy]propyl]phenyl]-estra-4.9-diene-3,17-dione

To a solution of 3.41 g of11β-[4-(3-hydroxypropyl)phenyl]estra-4.9-diene-3,17-dione prepared topreparation 1 in 30 ml of CH₂Cl₂, under inert atmosphere and at ambienttemperature, 1.53 ml of TEA and 0.72 ml of sulfonyl methane chloride insolution in 2 ml of CH₂Cl₂ is added whilst maintaining the temperatureat 0-5° C. and stirring at this temperature. After washing and drying itis evaporated under reduced pressure until 4.15 g of expected rawproduct is obtained.

F = 196° C. Rf (CH₂Cl₂/Acetone 8/2): 0.51 RMN (CDCl3) 300 MHZ 0.54(s)CH₃ in 18 3.00(s) OSO₂CH ₃ 4.21(t) J = 5.5 CH ₂—OSO₂ CH₃ 4.41(dl) J = 7H11 5.80(s) H4 7.11 H aromatics

Stage B: Aromatisation of Ring A ps3-hydroxy-11β-[4-[3-[(methylsulfonyl)oxy]propyl]phenyl]estra-1,3,5(10)-trien-17-one

a) Aromatisation

To a solution of 4.15 g of dienone prepared in the preceding stage in 40ml of CH₂Cl₂, under inert atmosphere and at ambient temperature, whilstcooling in an ice bath, 4 ml of acetic anhydride and 2 ml of acetylbromide is added and stirred for 1 hour.

b) Saponification

It is evaporated under reduced pressure, 20 ml of THF is added underinert atmosphere and 20 ml of methanol then 28 ml of soda 2N is addedwhilst cooling in an ice bath. It is stirred for 40 mn, acidified withchlorhydric acid 2N, drawn off with ethyl acetate, washed in salt waterthen evaporated under reduced pressure until 4.54 g of raw product isobtained that is purified by chromatography by eluting with theCH₂Cl₂/AcOEt 9/1 compound. 3.18 g of expected product is obtained and590 mg of a second product (3-ceto -5(10),9(11)-diene).

Rf (CH₂Cl₂/AcOEt 9/1): 0.23 RMN (CDCl₃) 300 MHz 0.43(s) CH₃ in 182.92(s) OSO₂CH ₃ 4.02(m) H11 4.12(m) CH ₂—OSO₂— 4.61(s) OH in 3 6.41(dd)H2 6.61 H4 6.81(d) H1 6.89 and 7.01 H aromatics

Stage C: Introduction of the Amine

3-hydroxy-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

To a solution of 1.45 g of mesylate prepared in stage B in 15 ml of THF,under inert atmosphere and at ambient temperature, 2.96 ml of piperidineis added, brought to reflux for 3 hrs, returned to ambient temperature,ethyl acetate is added, it is washed with sodium bicarbonate, with saltwater then evaporated under reduced pressure until 1.48 g of raw productis obtained that is purified by chromatography by eluting with thecompound CH₂Cl₂/AcOEt/NH₄OH 90/10/0.5. 1.2 g of expected product isobtained.

Rf(CH₂Cl₂/ACOEt/NH₄OH 90/10/0.5) 0.35 RMN(CDCl₃) 300 MHz 0.44(s) CH₃ in18 1.59 N—CH₂—CH ₂ of the ring 2.41 N—CH ₂—CH₂ of the ring 4.02(tl) H116.31(dd) H2 6.52(d) H4 6.77(d) H1 ˜6.81 and ˜6.98 H aromatics

EXAMPLE 2 3-hydroxy-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]estra-1,3,5(10)-trien-17-one

It is carried out as in example 1 stage C from 456 mg of the mesylateprepared in stage B of example 1 and 0.79 ml of pyrrolidine. 441 mg ofraw product is obtained that is purified by chromatography by elutingwith the AcOEt/TEA 7/3 compound then by crystallisation in isopropylicether. 347 mg of expected product is obtained.

F = 180° C. Rf(CH₂Cl₂/AcOEt/NH₄OH 9/1/0.5): 0.33 RMN(CDCl₃) 300 MHz0.44(s) CH₃ in 18 1.75 N—CH₂—CH ₂ of the ring 2.50 N—CH ₂—CH₂ of thering 4.03(tl) H11 6.25(dd) H2 6.51(d) H4 6.75(d) H1 ˜6.84 and ˜6.99 Haromatics

EXAMPLE 3 3-hydroxy-11β-[4-[3-dimethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

It is carried out as in example 1 but using dimethylamine as amine.

EXAMPLE 4 4-chloro-3-hydroxy-11β-[4-[3-(piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

Stage A: Chlorination

4-chloro-11β-[4-(3-hydroxypropyl)phenyl]estra-4.9-diene-3-one

To a solution of 11.9 g of11β-[4-(3-hydroxypropyl)phenyl]-estra-4.9-diene -3,17-dione prepared topreparation 1 in 100 ml of DMF, under inert atmosphere and at 60° C.,4.93 g of N-chloro succinimide is added and stirred for 10 mn at thistemperature. It is poured into water, drawn off, washed, dried,evaporated under reduced pressure until 16.2 g of raw expected productis obtained that is purified by chromatography by eluting with thecompound CH₂Cl₂/Acetone 85/15. 9.34 g of pure expected product isobtained.

Rf(CH₂Cl₂/Acetone 85/15 RMN CDCl₃) 300 MHZ 0.56(s) CH₃ in 18 3.24(dt) Hequatorial 3.65(t) CH ₂—OH 4.42(d) H11 ˜7.09 H aromatics

Stage B: Formation of Mesylate

4-chloro-11β-[4-[3-[(methylsulfonyl)oxy]propyl]phenyl]-estra-4.9-diene-3-one

To a solution of 9.34 g of alcohol prepared in stage A in 90 ml ofCH₂Cl₂, under inert atmosphere and at ambient temperature, 3.86 ml ofTEA and 1.82 ml of sulfonyl methane chloride in solution in 5 ml ofCH₂Cl₂ is added whilst maintaining the temperature at 0-5° C. andstirring for 30 mn at this temperature. After washing and drying it isevaporated under reduced pressure until 11 g of expected raw product isproduced.

Rf(CH₂Cl₂/Acetone 85/15): 0.3 RMN(CDCl₃) 250 MHz 0.56(s) CH₃ in 183.00(s) OSO₂CH₃ 3.26(dt) H equatorial 4.22(t) CH ₂—OSO₂CH₃ 4.42(dl) H11˜7.10 H aromatics

Stage C: Aromatisation of Ring A

4-chloro-3-hydroxy-11β-[4-[3-[(methanesulfonyl)oxy]propyl]-phenyl-estra-1,3,5(10)-trien-17-one

a) Aromatisation

To a solution of 10.37 g of dienone prepared in the preceding stage in100 ml of CH₂Cl₂, under inert atmosphere and at ambient temperature,whilst cooling in an ice bath, 10 ml of acetic anhydride and 2 ml ofacetyl bromide, is added and stirred for 6 hours at ambient temperature.

b) Saponification

It is evaporated under reduced pressure, 50 ml of THF is added, 50 ml ofmethanol then 70 ml of Soda 2N is added whilst cooling in an ice bath.It is stirred for 45 mn, acidified with 70 ml of chlorohydric acid 2N,drawn off in ethyl acetate, washed in salt water then evaporated underreduced pressure until 11.5 g of raw product is obtained that ispurified by chromatography by eluting with the cyclohexane/AcOEt 9/1compound. 6 g of expected product is obtained (Rf=0.27) and 768 mg of asecond product (4-chloro-1,3,5(10), 9(11) tetraenone derivative notcontaining hydroxy in 3 (Rf=0.39)).

Rf(CH₂Cl₂/AcOEt 9/1): 0.27 RMN(CDCl₃) 250 MHZ 0.43(s) CH₃ in 18 2.93(s)OSO₂CH ₃ 4.02(m) H11 4.14 CH ₂—OSO₂ 5.46(s) OH in 3 6.64 H2 6.81 H1 6.92H aromatics

Stage D: Introduction of the Amine

4-chloro-3-hydroxy-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

To a solution of 1.5 g of mesylate prepared in the preceding stage in 15ml of THF, under inert atmosphere and at ambient temperature, 2.96 ml ofpiperidine is added, brought to reflux for 3 hrs, brought back toambient temperature, ethyl acetate is added, it is washed with sodiumbicarbonate, with salt water then evaporated under reduced pressureuntil 1.66 g of raw product is obtained that is purified bychromatography by eluting with the compound CH₂Cl₂/MeOH/NH₄OH90/10/0.5.1.2 g of expected product is obtained.

Rf(CH₂Cl₂/AcOEt/NH₄OH 90/10/0O.5): 0.27 RMN(CDCl₃) 300 MHZ 0.43(s) CH₃in 18 1.62 N—CH₂—CH ₂ of the ring 2.46 N—CH ₂—CH₂ of the ring 4.01(tl)H11 6.61(d) H2 6.79(d) H1 ˜6.89 H aromatics

EXAMPLE 54-chloro-3-hydroxy-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

It is carried out as in example 4 stage D but from 517 mg of mesylate(example 4 stage C) and 0.84 ml of pyrrolidine.

510 mg of raw product is obtained that is purified by chromatography byeluting with the compound CH₂Cl₂/MeOH/NH₄OH 90/10/1. 380 mg of expectedproduct is obtained.

Rf(CH₂Cl₂/AcOEt/NH₄OH 90/10/1): 0.3 RMN(CDCl₃) 300 MHz 0.42(s) CH₃ in 181.75 N—CH₂—CH ₂ of the ring 2.46 N—CH ₂—CH₂ of the ring 4.02(sl) H116.56(d) H2 6.79(d) H1 6.89(AA′BB′) H aromatic

EXAMPLE 64-chloro-3-hydroxy-11β-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-17-one

It is carried out as in example 4 stage D but from 517 mg of mesylate(example 4 stage C) and 1 ml of diethylamine.

500 mg of raw product is obtained that is purified by chromatography byeluting with the compound CH₂Cl₂/MeOH/NH₄OH 90/10/1. 385 mg of expectedproduct is obtained.

Rf(CH₂Cl₂/AcOEt/NH₄OH 90/10/1): 0.31 RMN (CDCI3) 3OOMHz 0.42(s) CH₃ in18 0.95 N—CH₂—CH ₃ 2.49 N—CH ₂—CH₃ 4.02(t) H11 6.59(d) H2 6.80(d) H16.90(AA′BB′) H aromatics

EXAMPLE 7

11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

To a solution of 310 mg of the product obtained in example 2 in 3 ml ofmethanol, 54 mg of sodium borohydrure at 97% is added at 0-5° C.,stirred for 1 hour at this temperature, salt water is added, it is drawnoff, washed, dried and evaporated under reduced pressure until 320 mg ofraw product is obtained that is purified by chromatography by elutingwith the compound CH₂Cl₂/MeOH/NH₄OH 90/10/1. 217 mg of pure expectedproduct is obtained.

Rf (CH₂Cl₂/MeOH/NH₄OH): 0.23 RMN (CDCl₃) 300 MHz 0.33(s) CH₃ in 18 1.76N—CH₂—CH ₂ of the ring 2.52 N—CH ₂—CH₂ of the ring 3.69(dd) H17 3.96(tl)H11 6.27(dd) H2 6.47(d) H4 6.76(d) H1 ˜6.83 and ˜6.98 H aromatics

EXAMPLE 8

11β-[4-(3-diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien -3,17β-diol

It is carried out as in example 7 (reduction with sodium borohydrure)but from the product obtained in example 3.

Rf AcOEt/iPrOH/NH₄OH 70/30/1: 0.17 RMN (CDCl₃ + 1 drop of C₅D₅N) 300 MHz0.32(s) CH₃ in 18 2.18(s) N—CH ₃ 3.67 H17 3.95 H11 6.46(dd) H2 6.64(d)H4 6.81(d) H1 ˜6.88˜7.00 H aromatics

EXAMPLE 9

11β-[4-(1-piperidynyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

It is carried out as in example 7 (reduction with sodium borohydrure)but from the product obtained in example 1.

Rf ethyl acetate/TEA 90/10: 0.30 RMN (CDCl₃) 300 MHz 0.33(s) CH₃ in 182.1 to 2.5 N—CH ₂, Ph—CH ₂ 3.70(dd) H17 3.96(tl) H11 6.32(dd) H2 6.47(d)H4 6.78(d) H1 ˜6.82˜6.98 H aromatics

EXAMPLE 10

4-chloro-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

It is carried out as in example 7 but from 257 mg of product obtained inexample 5 and 42 mg of sodium borohydrure at 97%. 221 mg of raw productis obtained that is purified by cristallisation to obtain 154 mg of pureexpected product.

Rf (CH₂Cl₂/MeOH/NH₄OH 90/10/1): 0.15 RMN (CDCl₃) 300 MHz 0.33(s) CH₃ in18 1.73(m) N—CH₂—CH ₂ of the ring ˜2.37; ˜2.50 N—CH₂ and PH—CH₂ of thechain 2.43(m) N—CH ₂—CH₂ of the ring 3.71(dd) H17 3.93(tl) H11 6.58(d)H2 6.76(d) H1 6.91 H aromatics

EXAMPLE 11

4-chloro-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

It is carried out as in example 7 but from 305 mg of product obtained inexample 4 and 48 mg of sodium borohydrure at 97%. 275 mg of raw productis obtained that is purified by crystallisation in acetone to obtain 170mg of pure expected product.

F = 128° C. Rf (CH₂/Cl₂MeOH/NH₄OH 90/10/1): 0.25 RMN (CDCl₃) 300 MHz0.30(s) CH₃ in 18 1.55(m) N—CH₂—CH ₂ of the ring 2.23; 2.41 N—CH₂ andPh—CH₂ of the chain 2.36(m) N—CH ₂—CH₂ of the ring 3.68(dd) H17 3.95(t)H11 6.58(d) H2 6.79(d) H1 6.88 H aromatics

EXAMPLE 12 4-chloro-11β-[4-[3-(1-diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

It is carried out as in example 7 but from 262 mg of product obtained inexample 5 and 42 mg of sodium borohydrure at 97%. 231 mg of raw productis obtained that is purified by chromatography to obtain 223 mg of pureexpected product.

Rf (CH₂Cl₂/MeOH/NH₄OH 90/10/1): 0.18 RMN (CDCl₃) 300 MHz 0.30(S) CH₃ in18 0.95(t) N—CH₂—CH ₃ 2.49(q) N—CH ₂—CH₃ 3.69(t) H17 3.95(t) H11 6.57(d)H2 6.78(d) H1 6.91 H aromatics

EXAMPLE 13 17α-methyl-11β-[4-[3-(1-piperidininyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol

1.2 g of finely ground cerium chloride heptahydrate (CeC13, 7H2O), isheated for 2 hours under reduced pressure, brought to ambienttemperature under inert gas, 12 ml of THF is added, it is stirred for 2hours at ambient temperature then 1.9 ml of an etherised solution ofmethyllithium is added at −68° C. After having stirred for 30 mn at−72°C. 300 mg of the product of example 1 in solution in 3 ml of THF isadded. The temperature is left to rise to room temperature, then thesolution is filtered, washed, dried and evaporated under reducedpressure to obtain 325 mg of raw product that is purified bychromatography by eluting with the compound CH₂Cl₂/MeOH/NH₄OH 90/10/0.5.

Rf (CH₂Cl₂/MeOH/NH₄OH 90/10/0.5): 0.25 RMN (CDCl₃) 300 MHz 0.45(s) CH₃in 18 1.29 CH₃ in 17 4.00(tl) H11 6.35(dd) H2 6.49(d) H4 6.79(d) H1˜6.81 and ˜6.98 H aromatics

EXAMPLE 144-chloro-17α-methyl-11β-[4-[3-(1-piperidininyl)propyl]phenyl]-estra-1,3,5(10)-trien-11β-diol

It is carried out as in example 13 but from 300 mg of the productprepared in example 4 and 12 ml of an etherised solution ofmethyllithium. 312 mg of raw product is obtained that is purified bychromatography by eluting with the compound CH₂Cl₂/MeOH/NH₄OH 90/10/1 toobtain 275 mg of pure expected product

Rf (CH₂Cl₂/MeOH/NH₄OH 90/10/1): 0.25 RMN (CDCl₃) 300 MHz 0.45(s) CH₃ in18 1.29(s) CH₃ in 17 1.56(m) N—CH₂—CH ₂ (ring) 2.34(m) N—CH ₂—CH₂ (ring)2.26(m) and 2.46(t) CH₂—N and CH₂—Ph (chain) 3.99(tl) H11 6.59(d, J = 8,5 Hz) H2 68(d) H1 ˜6.87 H aromatics

EXAMPLE 1511β-[4-[3-(1-piperidininyl)propyl]phenyl]-17α-(trifluoromethyl)-estra-1,3,5(10)-trien-3,17β-diol

1) Preparation of the 17β-trimethylsilyloxy, 17β-trifluormethyl

83 mg of tetrahydrated tetramethylammonium fluoride is dried for 2 hoursat 120° C., brought to ambient temperature under inert gas and 236 mg ofthe product of example 1, 3 ml of THF, and 0.3 ml of trimethyl(trifluoromethyl) silane (CF₃SiMe₃) is added whilst maintaining thetemperature at 0-5° C. The temperature is left to rise to 10° C. and itis stirred for 2 hours 30 at 0-5° C., then it is poured into salt water,drawn off, washed, dried and evaporated under reduced pressure to obtain340 mg of raw product.

2) Deprotection of the Alcohol

To a solution of 340 mg of previously obtained raw product in 4 ml ofTHF, under inert atmosphere and at room temperature, 2 ml ofterabutylammonium fluoride in solution 1 M in the THF is added, stirredfor 2 hours at room temperature, poured into water, drawn off, washed,dried and evaporated under reduced pressure until 530 mg of raw productis obtained that is purified by chromatography by eluting with thecompound CH₂Cl₂/MeOH/NH₄OH 90/10/1 then with the compound AcOEt/TEA95/5. 96 mg of pure expected product is obtained.

Rf (AcOEt/TEA 95/5): 0.25 RMN (CDCl₃) 300 MHz 0.50(s) CH₃ in 18 4.03(tl)H11 6.36(dd) H2 6.52(dd) H4 6.78(d) H1 ˜6.85 and ˜6.96 H aromatics

EXAMPLE 16 (17R)11β-[4-[3-(dimethylamino)propyl)phenyl]-spiro-(estra-1,3,5(10)-trien-17,2′(5′H)-furan)-3-ol

It is carried out as in example 1 but from dimethylamine and11β-[4-[3-hydroxypropyl)phenyl]-spiro-estra-4.9-diene-17,2′(5′H)-furan)-3-one.

EXAMPLE 17(17R)4′,5′dihydro-11β-[4-[3-(dimethylamino)propyl)phenyl]-spiro-(estra-1,3,5(10)-trien-17,2′(3′H)-furan)-3-ol

The reduction is carried out by hydrogenation of the product of example16 with palladium at 10% on carbon.

Rf (AcOEt/TEA 8/2): 0.25 RMN (CDCl₃) 300 MHz 0.46(s) CH₃ in 18 2.20(s)N—CH ₃ 3.76(m) H′3 3.98(m) H11 6.32(dd) H2 6.47(d) H4 6.78(d) H1˜6.83˜6.97 H aromatics

Pharmacological Tests

1—Effect on the Proliferation of Mammary Cells

The proliferative activity of the molecules is studied comparativelywith that of oestradiol on the human mammary cells MCF-7 in culture.

To highlight the agonist effect of oestradiol and/or the moleculestested, the culture medium for the maintenance of the cells (rich ingrowth factors and in steroids) is replaced by a more impoverishedmedium, amongst others lacking in steroids (DMEM supplemented by 5% ofserum with steroid removed and without phenol red). The cells undergothis deprivation two days before the start of the trial.

After 7 days of culture in the presence of the products to be studied,the cellular proliferation is evaluated by quantitive analysis of theDNA. In each trial, the effect of the oestradiol at 10⁻¹⁰M (cellulargrowth in the presence of oestradiol less cellular growth in thepresence of solvent) determines the agonist activity at 100%. Theactivity of the molecules is evaluated in comparison to this internalcontrol. The molecules inducing a cellular growth identical to thatobserved with the solvent alone are classed “inactivated”, thoseinducing cellular growth lower than that observed with the solvent areclassed “inhibitor”.

ACTIVITY Oestradiol Agonist Example 12 Inhibitor Example 7 InhibitorExample 9 Inhibitor Example 13 Inhibitor Example 11 Mixed *Mixed: slightagonist activity in very weak concentrations and inhibitory activity instronger concentrations.

Conclusion

The products tested are not agonist of the growth of MCF-7 cells,certain ones are even inhibitors of these.

2—Affinity of the Human Oestrogen Receptor (REH)

A cytosolic extract of SF9 cells containing the recombinant humanoestrogen receptor is obtained by over-expression in aninsect-Baculo-viros system of cells, according to the generalmethodology described by N. R. WEBB et al. (Journal of Methods in celland Molecular Biology, (1990) vol 2 n°4, 173-188) and whose applicationis described for the expression of human hormonal receptors, for examplethe human glucocorticoid receptor (G.SRINIVASAN et al. MolecularEndocrinology (1990) vol 4 n°2 209-216).

The BaculoGold Transfection Kit (PharMingen, reference 21000K) is usedto generate the recombinant baculovirus containing the fragment of DNAcdescribed in the expression vector HEGO by L. TORA et al. (The EMBOJournal (1989) vol 8 n°7 1981-1986) comprising the coding region for thehuman oestrogen receptor of wild type with glycine in position 400.

The recombinant virus obtained in this way is used to express theprogestogen receptor in the cells of insects SF9 (ATCC CRL1711),according to the known methodology previously cited.

2×10⁷ SF9 cells are cultivated in a 175 cm² “Falcon” flask in TNM-FH“SIGMA” medium supplemented with 10% of foetal calf serum (FCS) and 50micrograms/ml of gentamycine. After infection then incubation at 27° C.for 40 to 42 hours, the cells are lysed in 1 ml of lyse buffer (Tris 20mM-HCl pH8, EDTA 0.5 mM, DTT 2mM, Glycerol 20%, KCl 400 mM) by afreezing-defrosting cycle that is repeated twice more. The supernatant,containing the recombinant human oestrogen receptor is preserved inliquid nitrogen in 0.5 ml amounts.

The supernatant is incubated at 0° C. for 24 hours with a consistentconcentration (T) of oestradiol tritiated in the presence of growingconcentrations either of cold oestradiol (0-1000×10⁻⁹M), or of coldproduct to be tested (0-25000×10⁻⁹M). The concentration of linkedtriated oestradiol (B) is then measured in each incubation by thedextran carbon adsorption technique.

3—Calculation of the Affinity Relative to Linking (ARL)

The 2 following curves are plotted: the percentage of 100×B/BO linkedtritiated hormone in comparison to the logarithm of the concentration ofcold reference hormone or in comparison to the logarithm of theconcentration of cold product tested.

The soundness of the following equation is determined:

I₅₀=100(B₀/B₀+Bmin/B₀)/2=100(1+Bmin/B0)=50(1+Bmin/B₀)

B₀=Concentration of the linked tritiated hormone in the absence of anycold product,

B=Concentration of the linked tritiated hormone in the presence of an Xconcentration of cold product,

Bmin=Concentration of linked tritiated hormone for an incubation of thistritiated hormone in concentration (T) in the presence of a large excessof cold reference hormone (1000×10⁻⁹) for human receptor.

The intersections of the right angle I50 and the curves, make itpossible to evaluate the concentration of cold reference hormone (CH)and the tested cold product (CX) which inhibit 50% of the bond of thetritiated hormone on the receptor.

The relative affinity of the link (ARL) of the tested product isdetermined by the equation:

ARL=100(CH)/(CX)

The obtained results are the following:

EH oestradiol = 100 EXAMPLES 24 H 12 28  7 59  9 28 13 42 11 14

Conclusion

The tested products present good affinities for the human oestrogenreceptor.

What is claimed is:
 1. A compound selected from the group consisting ofa compound of the formula

wherein R₁ is selected from the group consisting of hydrogen,—(CH₂)_(m)-Ar, —CO-Ar, —(CH₂)_(m)-Alk and —COAlk, m is an integer from 1to 3, Ar is a substituted or unsubstituted carbocyclic aryl of 6 to 18carbon atoms, Alk is non-aromatic, substituted or unsubstituted alkyland cycloalkyl of up to 12 carbon atoms, R₂ is an unsaturated orsaturated hydrocarbon of up to 6 carbon atoms, D forms a saturated orunsaturated, unsubstituted or substituted pentagonal or hexagonal ring,X is halogen, n is an integer from 3 to 5, R₃ and R₄ are individuallyselected from the group consisting of hydrogen, —(CH₂)_(m)-Ar,—(CH₂)_(m)-Het and —(CH₂)_(m)-Alk or taken together form a non aromaticor aromatic, unsaturated or saturated, mono- or polycyclic heterocycleof 3 to 15 ring members and optionally containing 1 to 3 additionalheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur, Het is aromatic or non-aromatic, unsubstituted or substituted,unsaturated or saturated heterocyclic of 1 to 9 carbon atoms and 1 to 5heteroatoms selected from the group consisting of oxygen, sulfur andnitrogen, the substituents for Alk, Ar, Het and D being at least onemember of the group consisting of hydrogen, halogen, alkoxy, alklthio,—NH₂, alkylamino, dialkylaminoalkyl, dialkylaminoalkoxy, —OH, acyloxy ofan organic carboxylic acid of 1 to 6 carbon atoms, —COOH, salified—COOH, —COOAlk, —CN, —CF₃, aryl, arylalkyl, alkyl, alkenyl and alkynyl,and D may also be substituted with —O—(CH₂)_(m)-Ar, —O—(CO)Ar,—O—(CH₂)_(m)-Het, and —O—(CO)-Het and its addition salts with non-toxicpharmaceutically acceptable acids and bases.
 2. A compound of claim 1wherein D is a pentagonal ring of the formula

wherein R₂, m, Alk, Ar and Het are defined as in claim 1, R₅ is selectedfrom the group consisting of —OH, —O—(CH₂)_(m)-Alk and —O—(CO)-Alk, R₆is selected from the group consisting of hydrogen and alkyl, alkenyl andalkynyl of up to 6 carbon atoms.
 3. A compound of claim 1 having theformula

wherein X¹ is chloring or bromine, n¹ is 3, R¹ ₃ and R¹ ₄ areindividually alkyl of 1 to 6 carbon atoms or together with the nitrogenform a saturated mono- or polycyclic heterocycle of 3 to 15 ring membersand optionally containing an additional heteroatom selected from thegroup consisting of oxygen, sulfur and nitrogen and R¹ ₅ is selectedfrom the group consisting of —OH, —O—(CH₂)_(m)-Alk, —O—(CO)-Alk,—O—(CH₂)_(m)-Ar, —O—(CO)Ar, —O—(CH₂)_(m)-Het, and —O—(CO) and R¹ ₆ isselected from the group consisting of hydrogen and alkyl, alkenyl andalkynyl of up to 6 carbon atoms.
 4. A compound of claim 3 wherein R¹ ₅is —OH and R¹ ₆ is selected from the group consisting of hydrogen andsubstituted or unsubstituted alkyl, lakenyl and alkynyl of up to 6carbon atoms.
 5. A compound of claim 3 wherein X′ is chlorine, R¹ ₃ andR¹ ₄ are individually alkyl of 1 to 6 carbon atoms or together with thenitrogen form a member of the group consisting of

R¹ ₅ is —OH and R¹ ₆ is selected from the group consisting of hydrogenand unsubstituted or substituted alkyl, alkenyl and alkynyl of up to 6carbon atoms.
 6. A compound of claim 1 selected from the groupconsisting of4-chloro-3-hydroxy-11β-[4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-17-one4-chloro-3-hydroxy-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl-estra-1,3,5(10)-trien-17-one4-chloro-3-hydroxy-11β-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-17-one4-chloro-11β-[4-[3-(1-pyrrolidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol4-chloro-11β-[4-[3(piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-diol4-chloro-11β-[4-[3-(diethylamino)propyl]phenyl]-estra-1,3,5(10)-trien-3,17β-dioland4-chloro-17α-methyl-11β-4-[3-(1-piperidinyl)propyl]phenyl]-estra-1,3,5(10)-trien-3-17β-diol.7. A method of treating osteoporosis in warm-blooded animals comprisingadministering to warm-blooded animals in need thereof an amount of acompound of claim 1 sufficient to treat osteoporosis.
 8. a method oftreating menopausal symptoms in female warm-blooded animals comprisingadministering to warm-blooded animals in need thereof an amount of acompound of claim 1 sufficient to treat menopausal symptoms.
 9. A methodof treating menopausal symptoms in female warm-blooded animalscomprising administering to female warm-blooded animals in need thereofan amount of a compound of claim 6 and its non-toxic, pharmaceuticallyacceptable acid addition salts.